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1. 发明申请

WO1994000569A1 METHODS FOR PRODUCING TRANSGENIC NON-HUMAN ANIMALS HARBORING A YEAST ARTIFICIAL CHROMOSOME 审中-公开
标题翻译：用于生产转基因非人类动物的方法将人造物染色体
公开(公告)号：WO1994000569A1
公开(公告)日：1994-01-06
申请号：PCT/US1993005873
申请日：1993-06-18
申请人： GENPHARM INTERNATIONAL, INC. , CHOI, Theodore , LORING, Jeanne, F. , KAY, Robert, M.
发明人： GENPHARM INTERNATIONAL, INC.
IPC分类号： C12N15/00
CPC分类号： C12N15/88 , A01K67/0276 , A01K67/0278 , A01K2207/15 , A01K2217/00 , A01K2217/05 , A01K2217/075 , A01K2227/105 , A01K2267/0306 , A01K2267/0312 , C07K14/4711 , C07K16/00 , C07K2317/21 , C07K2317/52 , C12N15/8509
摘要： The present invention provides methods and compositions for transferring large transgene polynucleotides and unlinked selectable marker polynucleotides into eukaryotic cells by a novel method designated co-lipofection. The methods and compositions of the invention are used to produce novel transgenic non-human animals harboring large transgenes, such as a transgene comprising a human APP gene or human immunoglobulin gene.
摘要翻译：本发明提供了通过称为协同脂转染的新方法将大转基因多核苷酸和未连接的选择标记多核苷酸转移到真核细胞中的方法和组合物。本发明的方法和组合物用于产生携带大转基因的新型转基因非人动物，例如包含人APP基因或人免疫球蛋白基因的转基因。

2. 发明申请

WO1997013852A1 TRANSGENIC NON-HUMAN ANIMALS CAPABLE OF PRODUCING HETEROLOGOUS ANTIBODIES 审中-公开
标题翻译：可产生异位抗体的转基因非人动物
公开(公告)号：WO1997013852A1
公开(公告)日：1997-04-17
申请号：PCT/US1996016433
申请日：1996-10-10
申请人： GENPHARM INTERNATIONAL, INC. , LONBERG, Nils , KAY, Robert, M.
发明人： GENPHARM INTERNATIONAL, INC.
IPC分类号： C12N15/00
CPC分类号： C12N15/8509 , A01K67/0276 , A01K67/0278 , A01K2207/15 , A01K2217/00 , A01K2217/072 , A01K2217/075 , A01K2227/105 , A01K2267/01 , A01K2267/0368 , A61K38/00 , C07K14/7051 , C07K16/00 , C07K16/2812 , C07K16/3007 , C07K16/4266 , C07K2317/21 , C07K2317/24 , C07K2317/52 , C07K2317/56 , C07K2317/92 , C07K2319/00 , C12N5/163 , C12N15/00 , C12N15/113 , C12N15/85 , C12N15/87 , C12N15/90 , C12N15/907 , C12N2310/111 , C12N2800/206 , C12N2800/70 , C12N2830/30 , C12N2830/36 , C12N2830/85
摘要： The invention relates to transgenic non-human animals capable of producing heterologous antibodies and methods for producing human sequence antibodies which bind to human antigens with substantial affinity.
摘要翻译：本发明涉及能够产生异源抗体的转基因非人动物和用于产生具有显着亲和力结合人抗原的人序列抗体的方法。

3. 发明申请

WO1992022670A1 EARLY DETECTION OF TRANSGENIC EMBRYOS 审中-公开
标题翻译：早期检测转基因植物
公开(公告)号：WO1992022670A1
公开(公告)日：1992-12-23
申请号：PCT/US1991004149
申请日：1991-06-12
申请人： GENPHARM INTERNATIONAL, INC.
发明人： GENPHARM INTERNATIONAL, INC. , KRIMPENFORT, Paul , LEE, Sang, He , STRIJKER, Rein
IPC分类号： C12Q01/68
CPC分类号： A01K67/0275 , A01K2217/05 , C12Q1/683 , C12Q1/6841 , C12Q1/6879 , C12Q2521/331
摘要： The present invention provides methods, based on in situ hybridization and the polymerase chain reaction, for the early detection of integrated transgenes in the nuclear genome.
摘要翻译：本发明提供了基于原位杂交和聚合酶链式反应用于早期检测核基因组中整合的转基因的方法。

4. 发明申请

WO1992022647A1 EARLY DETECTION OF TRANSGENIC EMRYROS 审中-公开
标题翻译：早期检测转基因昆虫
公开(公告)号：WO1992022647A1
公开(公告)日：1992-12-23
申请号：PCT/US1992005097
申请日：1992-06-12
申请人： GENPHARM INTERNATIONAL, INC. , KRIMPENFORT, Paul , LEE, Sang, He , STRIJKER, Rein
发明人： GENPHARM INTERNATIONAL, INC.
IPC分类号： C12N15/00
CPC分类号： A01K67/0275 , A01K2217/05 , C12Q1/683 , C12Q1/6841 , C12Q1/6879 , C12Q2521/331
摘要： The present invention provides methods, based on in in situ hybridization and the polymerase chain reaction, for the early detection of integrated transgenes in the nuclear genome.
摘要翻译：本发明提供了基于原位杂交和聚合酶链式反应的方法，用于早期检测核基因组中的整合转基因。

5. 发明申请

WO1993025567A1 PRODUCTION OF RECOMBINANT POLYPEPTIDES BY BOVINE SPECIES AND TRANSGENIC METHODS 审中-公开
标题翻译：通过牛肉种和转基因方法生产重组多糖
公开(公告)号：WO1993025567A1
公开(公告)日：1993-12-23
申请号：PCT/US1993005724
申请日：1993-06-15
申请人： GENPHARM INTERNATIONAL, INC. , DEBOER, Herman, A. , STRIJKER, Rein , HEYNEKER, Herbert, L. , PLATENBURG, Gerard , LEE, Sang, He , PIEPER, Frank
发明人： GENPHARM INTERNATIONAL, INC.
IPC分类号： C07H21/00
CPC分类号： C12N15/8509 , A01K67/0278 , A01K2207/15 , A01K2217/00 , A01K2217/05 , A01K2227/101 , A01K2227/105 , A01K2267/01 , A23C9/20 , C07K14/4732 , C07K14/765 , C07K14/79 , C12N9/2462 , C12N9/6464 , C12N15/85 , C12N2830/008 , C12N2830/85 , C12Y304/21069
摘要： A transgene for producing recombinant polypeptides in the milk of transgenic bovine species comprises at least one expression regulation sequence, a secretory DNA sequence encoding a secretory signal sequence which is functional in mammary secretory cells of the bovine species and a recombinant DNA sequence encoding the recombinant polypeptide. Also included are methods for producing transgenic bovine species. The method includes introducing the above transgene into an embryonal target cell of a bovine species, transplanting the trangenic embryonic target cell formed thereby into a recipient bovine parent and indentifying at least one female offspring which is capable of producing the recombinant polypeptide in its milk. The invention also includes transgenic bovine species as well as the milk from such transgenic bovine species. Methods are also provided for producing transgenic non-human mammals having a desirable phenotype. The method comprises first methylating a transgene followed by introduction into fertilized oocytes. The oocytes are then cultured to form pre-implantation embryons. Thereafter, at least one cell is removed from each of the pre-implantation embryons and the DNA digested with a restriction endonuclease capable of cleaving the methylated transgene but incapable of cleaving the unmethylated form of the transgene.
摘要翻译：用于在转基因牛物种的乳中产生重组多肽的转基因包括至少一个表达调控序列，编码在牛物种的乳腺分泌细胞中有功能的分泌信号序列的分泌DNA序列和编码重组多肽的重组DNA序列。还包括用于生产转基因牛物种的方法。该方法包括将上述转基因导入牛种的胚胎靶细胞中，将由此形成的转基因胚胎靶细胞移植到受体牛的母体中，并鉴定能够在其乳中产生重组多肽的至少一个雌性后代。本发明还包括转基因牛物种以及来自这种转基因牛物种的牛奶。还提供了用于产生具有所需表型的转基因非人哺乳动物的方法。该方法首先将转基因甲基化，然后引入受精卵母细胞。然后培养卵母细胞以形成植入前胚胎。此后，从每个植入前胚胎中移除至少一个细胞，并用能够切割甲基化的转基因但不能切割未甲基化形式的转基因的限制性内切核酸酶消化的DNA。

6. 发明申请

WO1993012227A1 TRANSGENIC NON-HUMAN ANIMALS CAPABLE OF PRODUCING HETEROLOGOUS ANTIBODIES 审中-公开
标题翻译：可产生异位抗体的转基因非人动物
公开(公告)号：WO1993012227A1
公开(公告)日：1993-06-24
申请号：PCT/US1992010983
申请日：1992-12-17
申请人： GENPHARM INTERNATIONAL, INC. , LONBERG, Nils , KAY, Robert, M.
发明人： GENPHARM INTERNATIONAL, INC.
IPC分类号： C12N15/00
CPC分类号： A01K67/0276 , A01K67/0278 , A01K2207/15 , A01K2217/00 , A01K2217/05 , A01K2217/075 , A01K2227/105 , A01K2267/01 , A01K2267/03 , A01K2267/0381 , A61K38/00 , C07K16/00 , C07K16/2812 , C07K16/3007 , C07K16/4291 , C07K16/44 , C07K2317/21 , C07K2317/24 , C12N15/8509 , C12N15/90
摘要： The invention relates to transgenic non-human animals capable of producing heterologous antibodies and transgenic non-human animals having inactivated endogenous immunoglobulin genes. In one aspect of the invention, endogenous immunoglobulin genes are suppresed by antisense polynucleotides and/or by antiserum directed against endogenous immunoglobulins. Heterologous antibodies are encoded by immunoglobulin genes not normally found in the genome of that species of non-human animal. In one aspect of the invention, one or more transgenes containing sequences of unrearranged heterogolous human immunoglobulin heavy chains are introduced into a non-human animal thereby forming a transgenic animal capable of functionally rearranging transgenic immunoglobulin sequences and producing a repertoire of antibodies of various isotypes encoded by human immunoglobulin genes. Such heterologous human antibodies are produced in B-cells which are thereafter immortalized, e.g., by fusing with an immortalizing cell line such as a myeloma or by manipulating such B-cells by other techniques to perpetuate a cell line capable of producing a monoclonal heterologous antibody. The invention also relates to heavy and light chain immunoglobulin transgenes for making such transgenic non-human animals as well as methods and vectors for disrupting endogenous immunoglobulin loci in the transgenic animal.
摘要翻译：本发明涉及能够产生具有失活的内源免疫球蛋白基因的异源抗体和转基因非人动物的转基因非人动物。在本发明的一个方面，内源性免疫球蛋白基因被反义多核苷酸和/或针对内源性免疫球蛋白的抗血清抑制。异源抗体由非人动物种类的基因组中通常不存在的免疫球蛋白基因编码。在本发明的一个方面，将含有未经修饰的杂种人免疫球蛋白重链序列的一个或多个转基因导入非人动物，从而形成能够功能重排转基因免疫球蛋白序列的转基因动物，并产生编码的各种同种型的抗体谱库通过人免疫球蛋白基因。这样的异源人抗体是在B细胞中产生的，其后被永生化，例如通过与永生化细胞系如骨髓瘤融合，或者通过其它技术操纵这样的B细胞，使能够产生单克隆异源抗体的细胞系。本发明还涉及用于制备这种转基因非人动物的重链和轻链免疫球蛋白转基因以及用于破坏转基因动物内源性免疫球蛋白基因座的方法和载体。

7. 发明申请

WO1993004169A1 GENE TARGETING IN ANIMAL CELLS USING ISOGENIC DNA CONSTRUCTS 审中-公开
标题翻译：使用ISOGENIC DNA构建的动物细胞中的基因定位
公开(公告)号：WO1993004169A1
公开(公告)日：1993-03-04
申请号：PCT/US1992007184
申请日：1992-08-20
申请人： GENPHARM INTERNATIONAL, INC. , BERNS, Anton , ROBANUS MANDAG, Els , TE RIELE, Hein
发明人： GENPHARM INTERNATIONAL, INC.
IPC分类号： C12N15/00
CPC分类号： C12N15/85 , C12N15/902
摘要： The present invention provides novel methods for modifying the genome of an animal cell which typically comprise the steps of: constructing a DNA molecule in which desired sequence modifications are contained in a segment of DNA (a ''targeting DNA'') that is substantially isogenic with a DNA in the cell genome (a ''target DNA''); introducing the targeting DNA construct into the cell (e.g., by microinjection, electroporation, transfection, or calcium phosphate precipitation); and selecting cells in which the desired sequence modifications have been introduced into the genome via homologous recombination.
摘要翻译：本发明提供了修饰动物细胞基因组的新方法，其通常包括以下步骤：构建DNA分子，其中所需的序列修饰包含在基本上是同基因的DNA片段（“靶向DNA”）中在细胞基因组中具有DNA（“靶DNA”）; 将靶向DNA构建体引入细胞（例如通过显微注射，电穿孔，转染或磷酸钙沉淀）; 并且通过同源重组选择其中所需的序列修饰已导入基因组的细胞。

8. 发明申请

WO1996014436A1 METHOD FOR MAKING RECOMBINANT YEAST ARTIFICIAL CHROMOSOMES 审中-公开
标题翻译：制备重组人酵母人造色素的方法
公开(公告)号：WO1996014436A1
公开(公告)日：1996-05-17
申请号：PCT/US1995014966
申请日：1995-11-03
申请人： GENPHARM INTERNATIONAL, INC.
发明人： GENPHARM INTERNATIONAL, INC. , DUNN, Barbara , CHOI, Theodore, K.
IPC分类号： C12Q01/68
CPC分类号： C12N15/81 , C12N15/04
摘要： The present invention provides methods for construction of recombinant Yeast Articifial Chromosomes ("YAC") by homologous recombination between YACs during meiosis. In particular, conditions are provided for the step of mating haploid cells and for the step of spore analysis that increase the frequency of spores containing the desired recombinant YAC. The methods find particular use in constructing recombinant YACs between YACs that are incompatible when co-propagated in a diploid and/or that share homology regions of less than about 50 kilobases. Linking YACs, methods of their construction, and methods of their use are provided that allow facile construction of a YAC containing two or more discontinuous regions of DNA.
摘要翻译：本发明提供了通过减数分裂期间YACs之间的同源重组来构建重组酵母特征染色体（“YAC”）的方法。特别地，提供了配对单倍体细胞的步骤和用于增加含有所需重组YAC的孢子的频率的孢子分析步骤的条件。该方法特别用于构建在二倍体共转染和/或共享少于约50千碱基的同源区的YAC之间不相容的重组YAC。提供连接YAC，其构建方法及其使用方法，其允许容易地构建含有两个或更多个DNA不连续区域的YAC。

9. 发明申请

WO1994025585A1 TRANSGENIC NON-HUMAN ANIMALS CAPABLE OF PRODUCING HETEROLOGOUS ANTIBODIES 审中-公开
标题翻译：可产生异位抗体的转基因非人动物
公开(公告)号：WO1994025585A1
公开(公告)日：1994-11-10
申请号：PCT/US1994004580
申请日：1994-04-25
申请人： GENPHARM INTERNATIONAL, INC. , LONBERG, Nils , KAY, Robert, M.
发明人： GENPHARM INTERNATIONAL, INC.
IPC分类号： C12N15/00
CPC分类号： C12N15/8509 , A01K67/0278 , A01K2207/15 , A01K2217/00 , A01K2217/05 , A01K2217/30 , A01K2227/105 , A01K2267/01 , A61K38/00 , C07K16/00 , C07K16/2812 , C07K16/3007 , C07K16/4291 , C07K16/44 , C07K16/462 , C07K2317/24
摘要： The invention relates to transgenic non-human animals capable of producing heterologous antibodies and methods for producing human sequence antibodies which bind to human antigens with substantial affinity.
摘要翻译：本发明涉及能够产生异源抗体的转基因非人动物和用于产生具有显着亲和力结合人抗原的人序列抗体的方法。

10. 发明申请

WO1992003918A1 TRANSGENIC NON-HUMAN ANIMALS CAPABLE OF PRODUCING HETEROLOGOUS ANTIBODIES 审中-公开
标题翻译：可产生异位抗体的转基因非人动物
公开(公告)号：WO1992003918A1
公开(公告)日：1992-03-19
申请号：PCT/US1991006185
申请日：1991-08-28
申请人： GENPHARM INTERNATIONAL, INC. , LONBERG, Nils , KAY, Robert, M.
发明人： GENPHARM INTERNATIONAL, INC.
IPC分类号： A01H01/00
CPC分类号： C12N15/907 , A01K67/0278 , A01K2207/15 , A01K2217/00 , A01K2217/05 , A01K2227/105 , A01K2267/01 , A61K38/00 , C07K14/7051 , C07K16/00 , C07K16/2812 , C07K16/3007 , C07K16/4266 , C07K16/4291 , C07K16/44 , C07K2317/21 , C07K2317/24 , C07K2317/52 , C07K2317/56 , C12N5/163 , C12N15/00 , C12N15/85 , C12N15/8509 , C12N15/87 , C12N15/90 , C12N2830/008 , C12N2830/15 , C12N2830/36 , C12N2830/60 , C12N2840/44
摘要： The invention relates to transgenic non-human animals capable of producing heterologous antibodies, i.e., antibodies encoded by immunoglobulin heavy and light chain genes not normally found in the genome of that species of non-human animal. In one aspect of the invention, transgenes encoding unrearranged heterologous human immunoglobulin heavy and light chains are introduced into a non-human animal thereby forming a transgenic animal capable of producing antibodies encoded by human immunoglobulin genes. Such heterologous human antibodies are produced in B-cells which are thereafter immortalized, e.g., by fusing with an immortalizing cell line such as a myeloma or by manipulating such B-cells by other techniques to perpetuate a cell line capable of producing a monoclonal heterologous antibody. The invention also relates to heavy and light chain immunoglobulin transgenes for making such transgenic non-human animals as well as methods and vectors for disrupting endogenous immunoglobulin loci in the transgenic animal. The invention also includes methods to generate a synthetic immunoglobulin variable region gene segment repertoire used in transgene construction and methods to induce heterologous antibody production using animals containing heterologous rearranged or unrearranged heavy and light chain immunoglobulin transgenes.
摘要翻译：本发明涉及能够产生异源抗体的转基因非人动物，即由非人动物种类的基因组中通常不存在的免疫球蛋白重链和轻链基因编码的抗体。在本发明的一个方面，将编码未经修饰的异源人免疫球蛋白重链和轻链的转基因导入非人动物中，从而形成能产生人免疫球蛋白基因编码抗体的转基因动物。这样的异源人抗体是在B细胞中产生的，其后被永生化，例如通过与永生化细胞系如骨髓瘤融合，或者通过其它技术操纵这样的B细胞，使能够产生单克隆异源抗体的细胞系。本发明还涉及用于制备这种转基因非人动物的重链和轻链免疫球蛋白转基因以及用于破坏转基因动物内源性免疫球蛋白基因座的方法和载体。本发明还包括产生用于转基因构建的合成免疫球蛋白可变区基因片段谱的方法和使用含有异源重排或未重排的重链和轻链免疫球蛋白转基因的动物诱导异源抗体产生的方法。

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